Miguel-Ángel González-Moles

The cancer stem cell hypothesis applied to oral carcinoma

It has been proposed that the development of tumors is based exclusively on the activity of cancer stem cells (CSCs) leading to a new model of carcinogenesis, the CSC hypothesis, in opposition to the conventional model of clonal evolution. The new model may help to explain the high mortality of oral cancer, unchanged over the past decades, the low response to treatment and the tendency of oral squamous cell carcinoma (OSCC) patients to develop multiple tumors. However, a more profound understanding of the molecular pathways involved in maintaining the stem cell (SC) state and of their alterations is required to elucidate the mechanisms underlying the development of tumors and metastatic spread, but research into SC biopathology is hampered by the lack of specific markers for identifying SCs and CSCs in tissues and for establishing topographic relationships with their lineage. We review current knowledge on stem cells in relation to oral cancer, including their possible origins, focusing on the CSC hypothesis of oral tumorigenesis and attempts being made to identify oral stem cells.

The use of gene therapy vs. corticotomy surgery in accelerating orthodontic tooth movement

OBJECTIVE Alveolar corticotomy surgery is an adjunctive therapy for reducing orthodontic treatment duration. The activation pathways of bone resorption involved in the tooth movement (TM) process are directly linked to the receptor activator of the nuclear factor-kB ligand (RANKL). Whether similar molecular pathways through RANKL, are shared by the acceleratory TM process (corticotomy-induced or not), sustained acceleration would therefore be expected with transgenic overexpression of this factor. We hypothesize that maintaining transgenic overexpression of RANKL will accelerate TM under force over time rather than at the beginning of therapy only; this contrasts with the corticotomy procedure. MATERIAL AND METHODS We transfected the pcDNA3.1(+)-mRANKL transgene in vitro into NIH3T3 cells, then evaluated by PCR, Western blot and ex vivo resorption assay. Quantification of RANKL immunofluorescence, fluorescence-based tartrate-resistant acid phosphatase+ (TRAP+) osteoclast counts and histological analyses of the bone resorption area were performed and clinically correlated after a 32-day in vivo experiment comparing corticotomy and gene therapy. RESULTS In vitro experiments resulted in increased level of RANKL protein (46%, p<0.05) and greater mineral resorption (39%, p<0.05) compared to the controls. In vivo results showed increased RANKL immunoexpression for both corticotomy (twofold) and transfection groups (threefold) after 10 days. After 32 days, a similar result was obtained for the transfected group but not for the surgery group. These data correlate with the clinical effect of decelerating TM in the surgery group. CONCLUSIONS Selective gene therapy with RANKL has been experimentally tested as an alternative method to corticotomy surgery, showing higher effectiveness than surgical methods used for acceleratory purposes in orthodontics.

Potential role of HDAC inhibitors in cancer therapy: Insights into oral squamous cell carcinoma

Histone deacetylases (HDACs) are enzymes that are involved in the remodeling of chromatin and play a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypoacetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anti-cancer activities in preclinical studies. Many researchers have highlighted the need to determine specific HDAC isotypes related to different tumor types in order to develop selective drugs for specific isoforms and avoid side effects. We summarize recent advances in the understanding of the molecular events that underlie the epigenetic changes in different tissue carcinomas, focusing on oral squamous carcinoma. The role of epigenetics in oral squamous cancer remains poorly understood, and further descriptive studies of specific HDAC member alterations are required to form the basis for future clinical trials.

β-catenin in oral cancer: an update on current knowledge.

β-Catenin is a multiple function protein. These functions derive from its interactions with other cell proteins, both on the cell membrane, in the cytoplasm and in the nucleus. β-Catenin forms a complex with the adhesion molecule E-cadherin, promoting cell-cell adhesion and thereby preventing the cell dissociation that is required for cancer invasion and progression mechanisms. There is also a dynamic pool of cytoplasmic β-catenin that serves as connection between the extracellular microenvironment and the nucleus. Cytoplasmic β-catenin acts as a transcription factor for the nucleus in the canonical Wnt pathway, activating the transcription of various genes. Structural or functional alterations of β-catenin can promote cancer progression. This review addresses the current knowledge on the implications of β-catenin in the development of oral cancer.

Is Periodontitis a Risk Factor for Cognitive Impairment and Dementia? A Case‐Control Study

BACKGROUND Dementia is a multi-etiologic syndrome characterized by multiple cognitive deficits but not always by the presence of cognitive impairment. Cognitive impairment is associated with multiple non-modifiable risk factors but few modifiable factors. Epidemiologic studies have shown an association between periodontitis, a potentially modifiable risk factor, and cognitive impairment. The objective of this study is to determine whether clinical periodontitis is associated with the diagnosis of cognitive impairment/dementia after controlling for known risk factors, including age, sex, and education level. METHODS A case-control study was conducted in Granada, Spain, in two groups of dentate individuals aged >50 years: 1) cases with a firm diagnosis of mild cognitive impairment or dementia of any type or severity and 2) controls with no subjective memory loss complaints and a score >30 in the Phototest cognitive test (screening test for cognitive impairment). Periodontitis was evaluated by measuring tooth loss, plaque and bleeding indexes, probing depths, and clinical attachment loss (AL). RESULTS The study included 409 dentate adults, 180 with cognitive impairment and 229 without. A moderate and statistically significant association was observed between AL and cognitive impairment after controlling for age, sex, education level, oral hygiene habits, and hyperlipidemia (P = 0.049). No significant association was found between tooth loss and cognitive impairment. CONCLUSION Periodontitis appears to be associated with cognitive impairment after controlling for confounders such as age, sex, and education level.

Levels of scientific evidence of the quality of life in patients treated for oral cancer.

Treatments used in cancer of the oral cavity have great impact on the physical, psychological and functional state of patients. There has been increasingly interest in evaluating the health-related quality of life using questionnaires among patients treated FOR oral cancer. Up to our knowledge no review on this theme has incorporated the level of evidence of the single identified studies. The objective of the present study is to determinate results and conclusions about the health-related quality of life of these patients, in view of scientific evidence. In general, the diversity of designs, level of evidence and questionnaires used for their assessment does not affect results, which indicate a decline in the health-related quality of life after treatment. This decline is greater when the tumor is large in size, and when radiotherapy is used, though the situation is seen to improve over the span of a year. Questionnaires on health-related quality of life provide concrete information regarding the impact of cancer treatment on patients. Key words:Quality of life, oral cancer, questionnaire.

A descriptive epidemiologic study of cleft lip and palate in Spain

OBJECTIVE The purpose of this study was to investigate the distribution of different cleft patterns by sex, side of the cleft, and family history of clefts in a referral hospital in the south of Spain. STUDY DESIGN One hundred twenty-three consecutive cleft lip subjects, with or without palates, attending the Stomatology Unit in the Virgen del Rocío University Hospital and in the Virgen Macarena University Hospital from October 2009 to May 2010 were studied. RESULTS The unilateral complete cleft lip and palate (54.4%) was most frequently found, followed by the bilateral complete cleft lip and palate (16.3%). Male patients (60.97%) and the left side (41.46%) were the most affected. A positive family history was observed in 21.94% of subjects. CONCLUSIONS The most frequent profile in the affected population was male with left unilateral complete cleft lip and palate. The high incidence of family history of cleft on the fathers side prompts us to recommend further genetic research in this area.

Is oral cancer incidence among patients with oral lichen planus/oral lichenoid lesions underestimated?

BACKGROUND Oral lichen planus (OLP) and oral lichenoid lesions (OLL) are considered potentially malignant disorders with a cancer incidence of around 1% of cases, although this estimation is controversial. The aim of this study was to analyze the cancer incidence in a case series of patients with OLP and OLL and to explore clinicopathological aspects that may cause underestimation of the cancer incidence in these diseases. METHODS A retrospective study was conducted of 102 patients diagnosed with OLP (n = 21, 20.58%) or OLL (n = 81) between January 2006 and January 2016. Patients were informed of the risk of malignization and followed up annually. The number of sessions programmed for each patient was compared with the number actually attended. Follow-up was classified as complete (100% attendance), good (75-99%), moderate (25-74%), or poor (<25% attendance) compliance. RESULTS Cancer was developed by four patients (3.9%), three males and one male. One of these developed three carcinomas, which were diagnosed at the follow-up visit (two in lower gingiva, one in floor of mouth); one had OLL and the other three had OLP. The carcinoma developed in mucosal areas with no OLP or OLL involvement in three of these patients, while OLP and cancer were diagnosed simultaneously in the fourth. Of the six carcinomas diagnosed, five (83.3%) were T1 and one (16.7%) T2. None were N+, and all patients remain alive and disease-free. CONCLUSIONS The cancer incidence in OLP and OLL appears to be underestimated due to the strict exclusion criteria usually imposed.

Significance of cytoplasmic cyclin D1 expression in oral oncogenesis

OBJECTIVES To examine cytoplasmic cyclin D1 expression levels in oral carcinogenesis and evaluate their possible oncogenic significance and their clinicopathological and prognostic implications. MATERIALS AND METHODS Immunohistochemical analysis of 69 oral squamous cell carcinomas (OSCCs) was performed, revealing 23 with cytoplasmic cyclin D1 expression. We analyzed the association of the percentage of cyclin D1-positive cells and the intensity of expression with TNM classification, tumor stage, differentiation degree, cell morphology, and Ki-67 expression. RESULTS Cytoplasmic cyclin D1 expression was associated with advanced tumor stage, poor differentiation, elevated Ki-67 expression, and the presence of invasive cell morphology, indicators of a poor prognosis. An association was observed between nuclear and cytoplasmic expressions of cyclin D1. CONCLUSIONS Cytoplasmic expression of cyclin D1 appears to possess functions related to increased cell migration and invasion in OSCC.